Lactones of the cyclopentano-poly-hydro-phenanthrene series and process of making same



Patented Nov. 7, 1944 I T OFFICE LACTONES F THE CYCLOPENTANO-POLY- HYDRO PHENANTHRENE SERIES "AN 'BRGCES S- OF MAKING SAME I I ,Izcopold Rtz'i'ekazurim, Switzerlandassignor to V v I Products, Inc., Summit, j

Ciba Pharmaceutical N. J., a corporation No Drawing. Application MayZO, 1942,, Serial;

No. 443,838. In Switzerland June 14, 1941 '14 Claims. (o1. zen-239.5)

The genius of the squill glucosides and of the toad poisons are derivatives of the cyclopentano+ polyhydro-phenanthrene series which are characterized by having a'simple or double unsaturated fi-lactone group in the side chain. No synthetic process for the manufacture of such substances has previously been known.

- Experience has now shown that lactones of 'the cyclopentano-polyhydro-phenanthrene series can be obtained if functional derivatives of 0:,[3-1111- saturated acids of this series, which contain in the 'y-position to the substituted carboxyl group at least one methyl or methylene group, are condensed with functional derivatives of formic or oxalic acid, and the products of the reaction subjected to hydrolysis, lactonisation,,or reesterification or, in certain cases, decarboxylation.

Finally, the products of the condensation can be subjected at any stage of the process to the action of reducing agents.-

Suitable starting materials are esters," nitriles,}

amides or similar functional derivatives of 0a,}?- unsaturated acids of the cyclopentano-polyhydrophenanthrene series substituted anywhere in the cyclopentano-p o 1 y h ydro-phenanthrene radical w and containing at least one methyl or methylene group in the 'y-position to the substituted carboxyl group.

These starting materials have, for example, the following formulas:

RC '(IJ ZV in which It represents a radical containing the cyclopentano-p o l y h y d r o-phenanthrene .ring structure, X. a functionally S as initial products,

derivatives of A -3, 7, 12-t r i a c etoxy-norcholadienic acidgA '-3-'a"c e t 0 x y-2 1,22-dimethyl-nor-choladienic acidyor A -3-acetoXy- 21-methyl bisnor-a1lo-cholenic acid may be used These compounds can be obtained by methodsalready known, e. g. by intr'oducin'g adoublebond into the corresponding acids, by condensation of 20'-keto-pregnane derivativeswithu-halogen fatty acid derivatives, or

' (for the'preparation. of starting materials of the last mentioned type) by condensation of ketones with hydrogen cyanide and elimination of water, or from pregnane-zl-acidderivatives with acetaL dehyde and its-homo1ogues.-= V

As secondicomponents of. the reaction, functional derivatives of, formic oroxalic acid, e.-g. their esters, nitriles or amides-are used.

The condensation is carriedout in the presence of condensing agents suchasalkaline metals, their alcoholates, amides and similarly acting substances, if necessar'y'in the presenceof a solvent or diluent. A mixture may be obtained if the initial compound has. more; than one reactive 1 methyl or. methylene'group.

After the condensation, the products of the reaction are present in the form of enol salts or mixtures of enol salts, and must be lactonised by suitable treatment; vThiscan be effected, for example, by-the action of lactonising agents, e. g. acid agents, if necessary --after hydrolysis of the carbox-ylic acid derivative -grouping.c Instead of i using hydrolysing and-lactonisingagents, the lactone .can be formed withthe, 'aid, of reesterifying,

agents, whereby a total saponification is avoided. If oxalic -'acid derivatives are'used forthe condensation, decarboxylating means must generally be used before or after lactonisationp The, double unsaturated lactones obtained I this way may becconverted byreducing-agents,

e. g. by catalytic hydrogenation,. into partially reduced still unsaturated'or into saturated lactones. This reaction can, however,.be carried out at an earlier stage oftheprocess, e.:g'. before "lactonisation. 1 q 1 I The following scheme may serve to illustrate I the reactions described, without limiting the process in question.

where Y and Z represent thegroups previouslymentioned.

The products obtained are a-lactones whiclr. are: related to the genins of the squill glucosides and the toad poisons, or identical: with them, and hence of considerable therapeutic interest.

The following examples illustrate the invention, but are not to be regarded aslimitingaitrin any way.

Example 1 5.0 gms. acid methyl ester and 1.6 gins. ethyl oxalatearedissolved in absolute'ether and 1.4 gms. potassium,

methylate added. Themixture slowly'assumes a.- dark colour. It. is allowedto-stand-for 24 hours and then decomposed: with dilute acetic: acid.

The products of the reaction: are dissolved in.

ether, dried' and the ether: evaporated ofi.z The residue is treated warrmwith: hydrogen bromide and glacial acetic acidto which. some acetic an hydride has been added; The product of the reaction is precipitated by diluting: with. water; washed with an excess'ot water and sublimediin a high vacuum, whereby decarboxylation takes place. The sublimate is-purified chromatographically by absorption on aluminum oxide; The

A -3-acetoxy-21 hydroxy methylenenorcholadienic acid lactoneis obtained.

This may be subsequently'partially orcompletely hydrogenated;

In a similar way A-lactones can be obtained by starting from; for-example; the a e-unsaturated acid derivatives named in-the description:

Example? 2 4 gms. A -3-acetoxy-26-methyl-cholesta-- diene-26 carboxy1ic acid ethyl ester; obtained from norcholestenee3eol-25-one.:and 'bromo-pro picnic ethyl ester, by Reformatzkys reaction, and; subsequent elimination of water,, arevadded to: I- gm. of potassium: ethylate preparedinabsolute: ether. 2. gmsi 'of amyl formate are: then' added;.

the mixture. allowed to stand for: several. days:

shut: off from the: air and. finally decomposed with dilute hydrochloric: acid; The-product on the reaction isdissolved in ether and washed with ice-cold water; Afterevaporating oil-the: ether, an. amorphousresidue is obtained which, gives a. distinct; reactionwith ferric chloride; The:

product is very unstable and should be prefer-- ably worked up immediately- For-this:purpose, it is dissolved in alcoholic hydrochlorimacidlandi A -3-abetoxymor-choladienim warmed for a short time. The solvent is then evaporated ofi, and the residue acetylated with acetic anhydride. The product of the reaction is 20 distilled in ahighvacuum and subsequently purifiedchromatographic'ally. A mixture is obtained off of -m'ethyli-pf"- [Ai -3-acetoxy-cholenyl- (24) lpentadienolide, having, the formula:

l (T .0 q QHwoo-V 35, Q

and cn'fi' dimethy-l-w -['AP- -3-acetoxy-nomcho lenyl-(ZB)Jqoentariienolide havingthe formula:

omc'oo If esters of A -3a-hydroxy -ZL-methyh-bisa nor choladienic acid; (obtained from; ZI-methylpregnene:-3.-ol- 20 -oneiand: hydrocyanic. acidgwithu subsequent: elimination; of water amt hydrolysis) etio cholenyl-(179:1Ppentadienolide: is: obtained having the; following; formula:

group consisting: of 'flis radicali arev treatedinthe; same way; a'l-iA 3-acetoxy polyhydro-phenanthrene ringstructure', the other carbon atoms 2 of the? pyrone ring; insofar as= they.=- do. notbear" oxygen; carrying a: member: of"th'ehydrogen and!v a hydrocarbon-:1

'2. Compounds of the'cyclopentano polyhydrm phenanthrene series which are linked-at the:1-7"- position with the a'-position:of an a-pyrone', jthe other carbon atoms'of the pyrone ring, insofar as they do not bear oxygen, carryinga member of thegroup consisting of hydrogen and a hydrocarbonradical. v v 1' 3-." -Compounds of the formula wherein R represents a radical containing the cyclopentano-polyhydrophenanthrene ring structure linked at the 17-position to the lactone ring, and Y and'Z each represents a member of the group consisting of hydrogen and a hydrocarbon radical. t

4. The '-[A -3-acetoxy-etio 1 cholenyl -(17) pentadienolide of the formula 5. A process for the manufacture of a lactone of the cyclopentanopolyhydrophenanthrene series, which comprises condensing a member of the group consisting of the amides, esters and nitriles of the arr-unsaturated acids of the said series, which contains in 'y-position to the amide, ester or nitrile group a member of the class consisting-of one methyl group and one methylene group, and wherein the oz-, }8- and 'y-positions contain only carbon and hydrogen atoms, with a member of the group consisting of the amides, esters and nitriles of formic acid and oxalic acid, and treating the resultant product with lactonizing means.

6. A process for the manufacture of a lactone of the cyclopentanopolyhydrophenanthrene series, which comprises condensing a member of the group consisting of the amides, esters and series, which contains in "y -position to the amide,

ester or nitrile group a member of the class consisting of one methyl group and one methylene group, and wherein the a-, ,9- and 'y-positions contain only carbon and hydrogen atoms, with a member of the group consisting of the amides, esters and nitriles of formic acid and oxalic acid, and treating the resultant product with a lactonizing agent.

7. A process for the manufacture of a lactone of the cyclopentanopolyhydrophenanthrene se ries, which comprises condensing a member of the group consisting of the amides, esters and nitriles of the n p-unsaturated acids of the said series, which contains in 'y-position to the amide, ester or nitrile group a member of the class consisting of one methyl group and one methylene group, and wherein 'the a, ,B- and'y-positions contain only carbon and hydrogen atoms, with a member of the group consisting of the amides, esters and nitriles of formic acid and oxalic acid, and treating the resultant product with a hy-- drolyzing agent and then with a lactonizing agent.

8.- A: process" fo'rlthe' manufacture of. a' lactone of the cyc1opentanopolyhydrophenanthrene se ries, which comprises condensing a member of the group consisting of the amides, esters and nitriles of the nap-unsaturated acids of the said series, which 'contains-in-"y-position' to the amide,

ester ornitrileg-roup a inember of i the class con s'isting of 'on 'r'n'etliyl group and -one' methylene group, and-*whrei-ni-the --i-, 3- and -p'osi-tio'iis contain only carbon and hydrogen atoms, with a member of the group consisting of theamides. estersand nitriles of formic acid and oxalic acid, and treating the resultant product successively with a hydrolyzing agent, a lactonizing agent and a re-esterifying agent.

9. A process for the manufacture of a lactone of the cyclopentanopolyhydrophenanthrene series, which comprises condensing a member of the group consisting of the amides, esters and nitriles-of the aye-unsaturated acids of the said series, which contains in 'y-position to the amide, ester or nitrile group a member of the class consisting of one methyl group and one methylene ries, which comprises condensing a compound of the formula R-C=C-Z I wherein R represents a radical containingthe cyclopentanopolyhydrophenanthrene ring structure, X represents a member selected from the group consisting of the amide and ester groups and the nitrile radical, and Y and Z each represents a member of the group consisting of hydrogen and a hydrocarbon radical, with a member of the group consisting of the amides, esters and nitriles of formic acid and oxalic acid, and treating the resultant product with lactonizing means.

13. A process for the manufacture of a lactone of the cyclopentanopolyhydrophenanthrene series, which comprises condensing a compound of the formula wherein R represents a radical containing the cyclopentanopolyhydrophenanthrene ring structure, X represents a member selected from the group consisting of the amide and ester groups and the nitrile radical, and Y and Z each represents a member of the group consisting of hydrogen and a hydrocarbon radical, with a member of the group consisting of the amides, esters and nitriles of formic acid and oxalic acid,

and treating the resultant product with lactonizi ng means. I

l4. A process for the manufacture of a lactone cf 'the cyclopentanopolyhydrophenanthrene seriesamhinmcomuniseswondensinm aaoomnoundtof and'zthmnitmlar radica1,-; andififanizseacmreprem gma; seats; a; member of the-'-gmup; consistingzmfi RWEGY'LGFWZ; Imdrogem a hydrocarbon radical; with; a!

1; member; 05?. the ggoup; consist/ingot 'thBii amides;

estersmnmnitrdleswflformimacidandmxalit: acid: whmeimR mnresentsmayradinah containinuthe and: treating; the; resultant; product; with: Ian; cyclonentannpulyhxdmphenanbhmnm;rinsg'stnmtonizing means. X; nepxesents. ammembgn-zselectagi fzumcthe: LEQPOID: gtomscpnsisting vo1 thexamida'xandxiestan'ggoups 

